JP2015042669A - Slow-release cilostazol tablet having an improved elution rate and minimal side effects - Google Patents
Slow-release cilostazol tablet having an improved elution rate and minimal side effects Download PDFInfo
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Abstract
Description
本発明は、放出制御用高分子を使用して製造された薬理学的有効成分であるシルロスタゾールの徐放錠に関し、特に,１日１回の投与が可能であり、ｐＨ変化にも一定にシルロスタゾールの溶出率を制御して頭痛、頭重感、頻脈などのシルロスタゾールの副作用を減少させて錠製の服用便宜性を向上させたシルロスタゾール徐放錠に関する。 The present invention relates to a sustained-release tablet of sillostazol, which is a pharmacologically active ingredient produced using a release controlling polymer, and in particular, it can be administered once a day, and silylstazole can be kept constant even with changes in pH. The present invention relates to a sustained release tablet of sillostazol, which controls the dissolution rate of the drug to reduce the side effects of sillostazol such as headache, head sensation, and tachycardia, thereby improving the convenience of taking the tablet.
キノリノン(ｑｕｉｎｏｌｉｎｏｎｅ)系列の物質であるシルロスタゾール(６−〔４−(シクロヘキシル−１Ｈ−テトラゾール−５−イル)ブトキシ〕−３,４−ジヒドロ−２(１Ｈ)-キノリノン、化１)は、ホスホジエステラーゼタイプ(ｐｈｏｓｐｈｏｄｉｅｓｔｅｒａｓｅ ｔｙｐｅ)を阻害することで、血小板凝集を抑制して血管の弛緩を促進する効能がある。また、血管内皮で遊走した血管平滑筋の細胞増殖を抑制することで、動脈硬化などの予防にも有用であると知られている。 Sillostazol (6- [4- (cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydro-2 (1H) -quinolinone, chemical 1), a quinolinone family of substances, is a phosphodiesterase type Inhibiting (phosphodiesterase type) has the effect of suppressing platelet aggregation and promoting relaxation of blood vessels. It is also known to be useful for preventing arteriosclerosis and the like by suppressing cell proliferation of vascular smooth muscle that has migrated on the vascular endothelium.
シルロスタゾールは、マウス、ラット、兎、犬と人間から分離した血小板において、ＡＤＰ，エピネフリン(ｅｐｉｎｅｐｈｒｉｎｅ)などにより誘導される血小板の一次凝集を抑制して血小板凝集塊を解離させる。また、ビーグル犬に経口投与する場合、ＡＤＰ、コラーゲンにより誘導される血小板の凝集を抑制し、慢性動脈閉塞症(バージャー病、閉塞性動脈硬化症、糖尿病性グ末梢血管病症など)患者に経口投与する場合、分離した血小板においてＡＤＰ、コラーゲン、アラキドン酸(ａｒａｃｈｉｄｏｎｉｃ ａｃｉｄ)そしてエピネフリンで誘導した血小板の凝集を抑制する。シルロスタゾールの血小板の凝集抑制効果は、投与後に迅速に発現し、繰り返し投与でもその効果を維持する。投与中止時の抑制された血小板凝集は、血漿中の濃度減少と共に投与前の数値に回復され、リバウンド現象(凝集亢進)は現われない。 Sillostazol suppresses the primary aggregation of platelets induced by ADP, epinephrine, etc. in platelets isolated from mice, rats, rabbits, dogs and humans, and dissociates platelet aggregates. In addition, when orally administered to beagle dogs, it suppresses platelet aggregation induced by ADP and collagen, and orally administered to patients with chronic arterial occlusion (such as Buerger's disease, obstructive arteriosclerosis, diabetic peripheral vascular disease) In this case, the aggregation of platelets induced by ADP, collagen, arachidonic acid and epinephrine is suppressed in the separated platelets. The effect of sillostazol on platelet aggregation appears rapidly after administration, and the effect is maintained even after repeated administration. Suppressed platelet aggregation at the time of discontinuation is restored to the pre-dose value as the plasma concentration decreases, and the rebound phenomenon (enhanced aggregation) does not appear.
シルロスタゾールの作用機序は次のようである。兎の血小板でセロトニン(ｓｅｒｏｔｏｎｉｎ)の放出を抑制するが、セロトニン、アデノシン(ａｄｅｎｏｓｉｎｅ)が血小板に入ることには影響を及ぼさない。血小板のアラキドン酸代謝に影響をかけないでＴＸＡ２(ｔｈｒｏｍｂｏｘａｎｅ Ａ２)による血小板凝集を抑制する。これは血小板と血管平滑筋のｃＡＭＰ−ＰＤＥ(ｃｙｃｌｉｃ ＡＭＰｐｈｏｓｐｈｏｄｉｅｓｔｅｒａｓｅ)活性を阻害することであり、結局、抗血小板作用と血管拡張作用を発揮する。 The mechanism of action of sillostazol is as follows. Sputum platelets inhibit serotonin release but do not affect serotonin and adenosine entering platelets. It inhibits platelet aggregation by TXA2 (thromboxane A2) without affecting the platelet arachidonic acid metabolism. This is to inhibit cAMP-PDE (cyclic AMPphosphodiesterase) activity of platelets and vascular smooth muscles, and eventually exerts antiplatelet action and vasodilatory action.
既存のシルロスタゾール製剤は、１日２回服用する製剤として患者順応度の下がる短所があるだけではなく、シルロスタゾール速放性製剤の場合、経口投与時に速くて不均一に薬物が放出されて急激な血中濃度の上昇をもたらし、その結果、頭痛、頭重感、頻脈などの副作用を引き起こすと知られている(Ａｍ Ｊ Ｃａｒｄｉｏｌ ２００１;８７(ｓｕｐｐｌ):２８Ｄ−３３Ｄ及びアメリカ特許公開番号第２００２/００５８０６６参照)。また、シルロスタゾールは、難溶性であるだけではなく、小腸下部に行くほど吸収率が低下されるので、通常的な放出制御製剤の場合、全体的な生体利用率が減少する恐れがあり、ＰＣＴ特許公開ＷＯ２０００/５７８８１公報は、微細粉末形態のシルロスタゾールが分散剤(ｄｉｓｐｅｒｓｉｎｇ ａｇｅｎｔ)及び/または可溶剤とともに分散及び/または溶解された形態の製剤を利用してシルロスタゾールの小腸下部吸収率を増加させる方法を開示している。 The existing sillostazol formulation not only has the disadvantage of lowering the patient's adaptability as a formulation to be taken twice a day, but in the case of a rapid release formulation of sillostazol, rapid and uneven drug release during oral administration causes rapid blood It is known to cause an increase in medium concentration, resulting in side effects such as headache, head sensation, tachycardia (Am J Cardiol 2001; 87 (suppl): 28D-33D and US Patent Publication No. 2002/0058066). reference). Furthermore, sillostazol is not only sparingly soluble, but its absorption rate decreases as it goes to the lower part of the small intestine. Therefore, in the case of a general controlled-release preparation, the overall bioavailability may be reduced. Publication WO2000 / 57881 discloses a method of increasing the absorption rate of silostazol in the small intestine using a preparation in which fine powder form of sillostazol is dispersed and / or dissolved together with a dispersing agent and / or a solubilizing agent. Disclosure.
既存のシルロスタゾール錠製は、服用直後の高い溶出率により頭痛、頭重感、頻脈などの副作用を有しているので、徐放錠に製造される必要性があり、単純に薬物の放出を遅延させる効果だけではなく、１日１錠の服用に合わせる一定な溶出率を示すシルロスタゾール徐放錠の開発が必要である。 Existing sillostazol tablets have side effects such as headache, head sensation, and tachycardia due to the high dissolution rate immediately after taking them, so they need to be manufactured into sustained-release tablets and simply delay the release of the drug It is necessary to develop a sustained release tablet of sillostazol that exhibits a certain dissolution rate that is not only effective for the purpose of taking 1 tablet per day.
したがって、本発明は前述のような問題点を解決するためになされたもので、既存の徐放錠製剤に使われた水溶性高分子のマトリックス形態の長所を有すると共に、腸で別途の制御システムが作用して薬物の放出制御が一定で精巧に行われることにより、生体内の血中濃度が一定に維持されて副作用の発現を抑制する製剤を提供することをその目的とする。 Accordingly, the present invention has been made to solve the above-described problems, and has the advantages of a matrix form of a water-soluble polymer used in existing sustained-release tablet formulations, and has a separate control system in the intestine. It is an object of the present invention to provide a preparation that suppresses the development of side effects by maintaining the blood concentration in the living body constant by controlling the release of the drug with constant and elaborate control.
上記の目的を達成するための本発明の適切な実施形態によれば、シルロスタゾール、放出制御用高分子、結合剤、充填剤及び滑沢剤を含有するシルロスタゾール徐放錠は、放出制御用高分子として、ヒドロキシプロピルメチルセルロース、カルボマー、ヒドロキシプロピルセルロース、メチルセルロース、ポリビニルピロリドン及びポリビニルアルコールから構成されたグループより選択された１種または２種以上の混合物を含む。 According to a suitable embodiment of the present invention for achieving the above object, a sustained release tablet of sillostazol containing sillostazol, a release controlling polymer, a binder, a filler and a lubricant is a release controlling polymer. As one or a mixture of two or more selected from the group consisting of hydroxypropyl methylcellulose, carbomer, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone and polyvinyl alcohol.
本発明の他の実施形態によれば、シルロスタゾール徐放錠に含まれた放出制御用高分子は、ヒドロキシプロピルセルロースとカルボマーの混合物である。 According to another embodiment of the present invention, the release controlling polymer contained in the sillostazol sustained release tablet is a mixture of hydroxypropylcellulose and carbomer.
本発明のまた他の実施形態によれば、シルロスタゾール徐放錠に含まれたヒドロキシプロピルメチルセルロースとカルボマーの混合物は、全体錠製重量に対して２５乃至５０重量％で含まれている。 According to another embodiment of the present invention, the mixture of hydroxypropylmethylcellulose and carbomer contained in the sillostazol sustained-release tablet is contained in an amount of 25 to 50% by weight based on the total tablet weight.
本発明のまた他の実施形態によれば、シルロスタゾール徐放錠に含まれた放出制御用高分子であるヒドロキシプロピルメチルセルロースの粘度は、８０,０００ｃｐｓ乃至１２０,０００ｃｐｓである。 According to still another embodiment of the present invention, the viscosity of hydroxypropyl methylcellulose, which is a release controlling polymer contained in the sillostazol sustained release tablet, is 80,000 cps to 120,000 cps.
本発明のまた他の実施形態によれば、シルロスタゾール徐放錠に含有されたヒドロキシプロピルメチルセルロースとカルボマー混合物の重量混合比は、１：１乃至２０：１である。 According to still another embodiment of the present invention, the weight mixing ratio of hydroxypropylmethylcellulose and carbomer mixture contained in the sillostazol sustained release tablet is 1: 1 to 20: 1.
本発明のシルロスタゾール徐放錠は、服用の便利性のために１日１回服用が可能な溶出時間を有し、既存のシルロスタゾール製剤の副作用である頭痛の発現を最小化した。また、本発明のシルロスタゾール徐放錠は、胃腸内のｐＨ変化にも均一な溶出率を維持する。 The sillostazol sustained-release tablet of the present invention has a dissolution time that can be taken once a day for convenience of administration, and minimizes the occurrence of headache, which is a side effect of the existing sillostazol preparation. Further, the sillostazol sustained-release tablet of the present invention maintains a uniform dissolution rate even in the pH change in the gastrointestinal tract.
本発明は、シルロスタゾール(ｃｉｌｏｓｔａｚｏｌ)を含有する徐放錠(ｓｕｓｔａｉｎｅｄ−ｒｅｌｅａｓｅ ｔａｂｌｅｔ)に関する。具体的には、１日１回服用が可能に溶出時間を延長し、水溶性マトリックスシステムで薬物の放出を制御し、ｐＨによって薬物の放出を調節することにより、胃から腸に至る薬物の吸収を一定で精巧に制御放出してシルロスタゾールの副作用の発現を抑制することで、女性や老人、児童の服用便宜性を向上させたシルロスタゾール徐放錠を提供する。 The present invention relates to sustained-release tablets containing cilostazol. Specifically, absorption of the drug from the stomach to the intestine is possible by extending the elution time so that it can be taken once a day, controlling the release of the drug with a water-soluble matrix system, and adjusting the release of the drug with pH. The present invention provides a sustained release tablet of sillostazol that improves the convenience of taking for women, the elderly, and children by suppressing the expression of side effects of sillostazol by controlling the release of the drug in a constant and elaborate manner.
本発明によるシルロスタゾール徐放錠は、シルロスタゾール、放出制御用高分子、結合剤、充填剤及び滑沢剤を含む。 The sillostazol sustained release tablet according to the present invention comprises sillostazol, a release controlling polymer, a binder, a filler and a lubricant.
放出制御用高分子では、薬剤学的に許容が可能な高分子であれば、いずれも使用でき、ヒドロキシプロピルメチルセルロース(Ｈｙｄｒｏｘｙｐｒｏｐｙｍｅｔｈｙｌｃｅｌｌｕｌｏｓｅ)、メチルセルロース(Ｍｅｔｈｙｌｃｅｌｌｕｌｏｓｅ)、エチルセルロース(Ｅｔｈｙｌｃｅｌｌｕｌｏｓｅ)、ヒドロキシプロピルセルロース(Ｈｙｄｒｏｐｒｏｐｙｌｍｅｔｈｙｌｃｅｌｌｕｌｏｓｅ)、カルボキシメチルセルロースナトリウム(Ｓｏｄｉｕｍ ｃａｒｂｏｘｙｍｅｔｈｙｌｃｅｌｌｕｌｏｓｅ)から構成されたセルロース誘導体、酸化プロピレン(ｐｒｏｐｙｌｅｎｅ ｏｘｉｄｅ)及びその誘導体、ポリビニルピロリドン(Ｐｏｌｙｖｉｎｙｌｐｙｒｒｏｌｉｄｏｎｅ、分子量９０、商品名ポビドンＫ−９０), ポリエチレングライコール(Ｐｏｌｙｅｔｈｙｌｅｎｅ ｇｌｙｃｏｌ)、ポリビニルアルコール(ｐｏｌｙｖｉｎｙｌ ａｌｃｏｈｏｌ)類、ポリビニルアセテート(Ｐｏｌｙｖｉｎｙｌａｃｅｔａｔｅ)、ポリビニルアセテートフタレート(Ｐｏｌｙｖｉｎｙｌａｃｅｔａｔｅ ｐｈｔｈａｌａｔｅ)、ポリメタクリレート(Ｐｏｌｙｍｅｔｈａｃｒｙｌａｔｅ)、ポリメタクリレートの重合体(商業的にＥｕｄｒａｇｉｔ、ポリアクリル酸(Ｐｏｌｙａｃｒｙｌｉｃａｃｉｄ))、ポリメタクリレートの誘導体(代表的にカルボマー)、グリセロールモノステアレート及びポロクサマーから構成されたグループより選択された１種または２種以上の混合物を使用することができる。好ましくは、ヒドロキシプロピルメチルセルロース、カルボマー、ヒドロキシプロピルセルロース、メチルセルロース、ポリビニルピロリドン及びポリビニルアルコールから構成されたグループより選択された１種または２種以上の混合物を使用することができ、より好ましくは、ヒドロキシプロピルセルロースとカルボマーの混合物を使うことができる。
Any pharmacologically acceptable polymer can be used as the release controlling polymer, such as hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, and hydropropylcellulose. Cellulose derivatives composed of sodium carboxymethylcellulose (propylene oxide) and its derivatives, polyvinylpyrrolidone (Polyvinylpyrrolidone,
本発明によるシルロスタゾール徐放錠に含まれた放出制御用高分子の全体錠製重量に対する割合は、２５％乃至５０％であることが好ましい。もし、放出制御用高分子の割合が２５重量％未満であれば、シルロスタゾールの放出時間が短くなり単位時間当り溶出量が多くなって副作用を発生し、５０重量％を超過すれば、シルロスタゾールの放出時間が長くなり単位時間当り薬物の溶出量が少なくて十分な薬効を期待することができない。 The ratio of the release controlling polymer contained in the sillostazol sustained release tablet according to the present invention to the total tablet weight is preferably 25% to 50%. If the ratio of the release-controlling polymer is less than 25% by weight, the release time of sillostazol is shortened and the amount of dissolution per unit time increases, causing side effects, and if it exceeds 50% by weight, the release of sillostazol is exceeded. Since the time is long and the amount of drug dissolved out per unit time is small, sufficient drug efficacy cannot be expected.
薬理学的有効成分の溶出を遅延させる徐放錠は、放出制御用高分子を混合して製造され、一般的にメチルセルロース、エチルセルロース、ヒドロキシメチルセルロース及びポリビニルピロリドンなどが放出制御用高分子で使われる。 Sustained-release tablets that delay the dissolution of pharmacologically active ingredients are produced by mixing release-controlling polymers. Generally, methylcellulose, ethylcellulose, hydroxymethylcellulose, polyvinylpyrrolidone, and the like are used as release-controlling polymers.
本発明者は、徐放錠の製造時に、一般的な放出制御用高分子にカルボマーを混合して使えば、単一成分の放出制御用高分子を使う場合に比べて長い溶出時間と一定な薬物溶出パターンを示すことを発見した。また、カルボマー以外の放出制御用高分子とカルボマーの重量比を調節することにより溶出パターンの調節が可能である事実も発見した。 The inventor of the present invention has a long dissolution time and a constant elution time when a carbomer is mixed with a general release-controlling polymer when a sustained-release tablet is produced, as compared with the case of using a single-component release-controlling polymer. It was found to show a drug dissolution pattern. We also discovered the fact that the elution pattern can be adjusted by adjusting the weight ratio of the carbomer to the release controlling polymer other than the carbomer.
シルロスタゾールの急速な溶出は、頻脈、頭重感や頭痛を引き起こすことができるので、一定な溶出率を維持・制御することも徐放錠において重要な要素である。ヒドロキシプロピルメチルセルロースは、錠製内に薬理学的有効成分の急速な溶出を防止するマトリックス(ｍａｔｒｉｘ)を形成して長い溶出時間を確保することができる。また、他の放出制御用高分子に比べて一定な溶出パターンを示す。 Since rapid dissolution of sillostazol can cause tachycardia, head sensation and headache, maintaining and controlling a constant dissolution rate is also an important factor in sustained release tablets. Hydroxypropyl methylcellulose can ensure a long dissolution time by forming a matrix that prevents rapid dissolution of the pharmacologically active ingredient in the tablet. In addition, it exhibits a constant elution pattern compared to other release controlling polymers.
薬理学的有効成分を含有した徐放錠の場合、溶出時に錠製の膨脹現象(ｓｗｅｌｌｉｎｇ)を示す。この場合、放出制御用高分子のマトリックスが堅固ではない場合、マトリックスが一部損傷(ｅｒｏｓｉｏｎ)されて錠製が崩解される現象が発生でき、これは急速な薬物放出につながって患者に頭痛や紅潮を誘発させる。このような問題点を解決するために、本発明では、放出制御用高分子として高粘度ヒドロキシプロピルメチルセルロースとカルボマーの混合物を使用した。カルボマーは、放出制御用高分子として、酸性条件である胃では、ゾル(ｓｏｌ)状態で存在して薬物放出がヒドロキシプロピルメチルセルロースシステムにより維持され、アルカリ条件である小腸では、ハイドロゲル(ｇｅｌ)状態で存在して薬物の放出を制御する。また、ヒドロキシプロピルメチルセルロースと共に使用する時、徐放錠内のマトリックスを堅固にする効果があり、錠製膨脹が形態を維持し、錠製のマトリックスを維持することにより、錠製の侵食(ｅｒｏｓｉｏｎ)を防止して一定な溶出率を維持する。 In the case of a sustained-release tablet containing a pharmacologically active ingredient, the tablet exhibits swelling phenomenon upon dissolution. In this case, if the matrix of the controlled-release polymer is not solid, a phenomenon may occur in which the matrix is partially eroded and the tablet is disintegrated, which leads to rapid drug release and causes headaches in the patient. Induces and flushes. In order to solve such problems, in the present invention, a mixture of high-viscosity hydroxypropylmethylcellulose and carbomer was used as a release controlling polymer. The carbomer is a release-controlling polymer that exists in the sol state in the stomach, which is in an acidic condition, and the drug release is maintained by the hydroxypropylmethylcellulose system, and in the small intestine, which is in an alkaline condition, in the hydrogel state. To control the release of drugs. Also, when used with hydroxypropylmethylcellulose, it has the effect of hardening the matrix within the sustained release tablet, and the tablet expansion maintains the form and the tablet erosion by maintaining the tablet matrix To maintain a constant dissolution rate.
本発明に使われたヒドロキシプロピルメチルセルロースは、粘度が８０,０００ｃｐｓ乃至１２０,０００ｃｐｓであり、好ましくは、９０,０００ｃｐｓ乃至１１０,０００ｃｐｓの粘度を有したヒドロキシプロピルメチルセルロースの使用が可能である。粘度が８０,０００ｃｐｓ未満であれば、多量のヒドロキシプロピルメチルセルロースが必要なので錠製のサイズが大きくなり、粘度が１２０,０００ｃｐｓを超過すれば、シルロスタゾールとの均一な混合が難しくなる。同一な粘度であっても粒子の粉砕度が一層一定で分散が優秀な物理的な形態(Ｐｈｙｓｉｃａｌ ｆｏｒｍ)が良い製品を使用する。 The hydroxypropyl methylcellulose used in the present invention has a viscosity of 80,000 cps to 120,000 cps, and preferably hydroxypropylmethylcellulose having a viscosity of 90,000 cps to 110,000 cps can be used. If the viscosity is less than 80,000 cps, a large amount of hydroxypropylmethylcellulose is required, so that the size of the tablet becomes large. If the viscosity exceeds 120,000 cps, uniform mixing with sillostazol becomes difficult. Even if the viscosity is the same, a product having a good physical form (physical form) in which the degree of pulverization of the particles is more constant and the dispersion is excellent is used.
本発明によるシルロスタゾール徐放錠に含有されるヒドロキシプロピルメチルセルロースとカルボマーの混合重量比は、１：１乃至２０：１である。１：１未満であれば、錠製内のマトリックス形成が難しくて薬物放出の遅延効果が低下し、２０：１を超過すれば、アルカリ条件でシルロスタゾールの溶出率が低下されシルロスタゾールと放出制御用高分子との間の均一な混合が難しい。好ましくは、１.５：１乃至１０：１の混合が可能である。 The mixing weight ratio of hydroxypropylmethylcellulose and carbomer contained in the sillostazol sustained-release tablet according to the present invention is 1: 1 to 20: 1. If the ratio is less than 1: 1, it is difficult to form a matrix in the tablet and the effect of delaying the drug release is lowered. If the ratio exceeds 20: 1, the dissolution rate of sillostazol is reduced under alkaline conditions, and the amount of sillostazol and release control is high. Uniform mixing between molecules is difficult. Preferably, a mixing of 1.5: 1 to 10: 1 is possible.
本発明によるシルロスタゾール徐放錠は、ｐＨの変化に従って一定な溶出率を示す。経口投与された徐放錠は、８時間以上人体内に滞留し、特に、長期間滞留する胃、小腸はｐＨの変化が非常に大きいので、徐放錠はｐＨによって一定な溶出率を維持しなければならない。本発明によるシルロスタゾール徐放錠は、ｐＨ１.２(人工胃液)とｐＨ６.８(人工膓液)において均一な溶出率を維持する。 The sillostazol sustained-release tablet according to the present invention exhibits a constant dissolution rate according to changes in pH. Orally administered sustained-release tablets stay in the human body for more than 8 hours, especially in the stomach and small intestine where they stay for a long time, because the pH changes are very large, so that the sustained-release tablets maintain a constant dissolution rate depending on the pH. There must be. The sillostazol sustained-release tablet according to the present invention maintains a uniform dissolution rate at pH 1.2 (artificial gastric juice) and pH 6.8 (artificial sputum).
本発明で使われる結合剤では、一般的に経口投与が可能なポリビニルピロリドン(分子量３０のものを利用、商品名ポビドンＫ−３０)またはその誘導体(ＰＶＰ)、ビニルピロリドン/ビニル誘導体の共重合体(ｃｏ−ｐｖｐ)及び澱粉類(ｓｔａｒｃｈ)などがあるが、それに制限されるものではない。分子量３０のポリビニルピロリドン(ポビドンＫ−３０)またはビニルピロリドン/ビニル誘導体の共重合体(ｃｏ−ｐｖｐ)が一番効果的であり、これらの混合物を利用することもできる。結合剤は、全体錠製重量対比３乃至１０重量％を含むことができ、結合剤を３重量％未満で添加する場合、結合力が弱くなって打錠が困難であり、１０重量％を超過して添加する場合、薬物の溶出率の調節が難しい。しかし、前記重量比に制限されるものではない。 The binder used in the present invention is generally polyvinyl pyrrolidone (with a molecular weight of 30; trade name povidone K-30) or a derivative thereof (PVP), a copolymer of vinyl pyrrolidone / vinyl derivative, which can be administered orally. (co-pvp) and starches, but are not limited thereto. Polyvinyl pyrrolidone (povidone K-30) having a molecular weight of 30 or a copolymer of vinyl pyrrolidone / vinyl derivative (co-pvp) is most effective, and a mixture thereof can also be used. The binder may include 3 to 10% by weight relative to the weight of the whole tablet. When the binder is added at less than 3% by weight, the binding force becomes weak and tableting is difficult, and the amount exceeds 10% by weight. Therefore, it is difficult to adjust the dissolution rate of the drug. However, the weight ratio is not limited.
本発明に使われる充填剤は、薬剤学的で通常使われる添加剤を含むことができる。このような添加剤では、ラクトース(Ｌａｃｔｏｓｅ)、砂糖(Ｓｕｇａｒ)、マンニトール(Ｍａｎｎｉｔｏｌ) 及びソルビトール(Ｓｏｒｂｉｔｏｌ)などを使用するか、またはこれらの混合物を使用することができ、必要によって、安定化剤及び保存剤を含むことができる。充填剤は、全体錠製重量対比１０乃至３０重量％を含むことができ、これに制限されるものではない。 The filler used in the present invention may contain pharmaceutically and commonly used additives. For such additives, lactose, sugar, sugar, mannitol and sorbitol can be used, or mixtures thereof can be used, optionally with stabilizers and Preservatives can be included. The filler may include 10 to 30% by weight based on the total tablet weight, but is not limited thereto.
本発明で使われる滑沢剤では、ステアリン酸マグネシウム(Ｍａｇｎｅｓｉｕｍ ｓｔｅａｒａｔｅ)、二酸化ケイ素(ＳｉＯ２)や非晶質ヒュームドシリカ(Ａｍｏｒｐｈｏｕｓ ｆｕｍｅｄｓｉｌｉｃａ)あるいはタルク(ｔａｌｃ)などを添加するか、またはこれらの混合物を添加することができ、これに制限されるものではない。滑沢剤は全体錠製重量対比１乃至５重量％を含むことができ、滑沢剤を１重量％未満で参加する場合、錠製の打錠が難しくなり、５重量％を超過して添加する場合、滑沢剤顆粒のコーティング現象によりシルロスタゾールの溶出様相に影響を及ぼす。しかし、前記重量比に制限されるものではない。 In the lubricant used in the present invention, magnesium stearate (Magnesium stearate), silicon dioxide (SiO 2 ), amorphous fumed silica (Amorphous fumed silica), talc or the like is added, or a mixture thereof. However, the present invention is not limited to this. Lubricants can contain 1 to 5% by weight of the total tablet weight, and if the lubricant is added at less than 1% by weight, tableting becomes difficult and added in excess of 5% by weight. In this case, the dissolution phenomenon of sillostazol is affected by the coating phenomenon of the lubricant granules. However, the weight ratio is not limited.
以下、実施例及び比較例を通じて本発明をより詳細に説明する。しかし、本発明の範囲はこのような実施例に制限されるものではない。 Hereinafter, the present invention will be described in more detail through examples and comparative examples. However, the scope of the present invention is not limited to such examples.
＜溶出率実験＞ <Elution rate experiment>
大韓薬典第７改訂の溶出試験法によって溶出試験した。溶出液では、ｐＨ７．８リン酸塩緩衝液を用い、溶出法は、パドル法を使用し、溶出液は、９００ｍｌ、撹拌速度は、１００ｒｐｍ、溶出温度は、３７±０.５℃で実行した。０、５、１０、１５、３０、４５、６０分に試料５ｍｌを取り同量の溶出液を加えた。分析条件は、上の溶出試験から得た液を０.４５μｍのメンブレンフィルターで濾過した液をＨＰＬＣを利用してアセクロフェナクを定量した。分析波長は、２７７ｎｍ、移動相は、アセトニトリル：ｐＨ７.４リン酸塩緩衝液＝６８:３２溶液であり、流速は、１.０ｍｌ/ｍｉｎ、コラムは、Ｃ１８ＯＤＳを使用した。 The dissolution test was conducted according to the dissolution test method of the 7th revision of the Korean Pharmacy. In the eluate, pH 7.8 phosphate buffer was used, the paddle method was used as the elution method, the eluate was 900 ml, the stirring speed was 100 rpm, and the elution temperature was 37 ± 0.5 ° C. . At 0, 5, 10, 15, 30, 45, and 60 minutes, 5 ml of the sample was taken and the same amount of eluate was added. As analysis conditions, aceclofenac was quantified by using a liquid obtained by filtering the liquid obtained from the above elution test through a 0.45 μm membrane filter using HPLC. The analysis wavelength was 277 nm, the mobile phase was acetonitrile: pH 7.4 phosphate buffer = 68: 32 solution, the flow rate was 1.0 ml / min, and the column used was C18 ODS.
(実施例１) (Example 1)
下記表に記載された各々の処方は、次のような製造方法を利用して徐放錠を製造した。まず、ポビドンＫ−３０とカルボマー(５０％)エタノールに分散・溶解させて結合液を調剤した。次に、スピードミキサーを使用してシルロスタゾール、微結晶セルロース、カルボマー(５０％)、ヒドロキシプロピルメチルセルロースをよく混合した後、結合液を利用して円筒状顆粒機で湿式顆粒を製造した。製造された前記顆粒物を乾燥オーブン(４０℃)で１２ｈｒ以上乾燥して４０ｍｅｓｈの篩で整粒した後、整粒した半製品に硬質無水珪酸とステアリン酸マグネシウムとを追加・混合して下記記載された１錠当りの重さに合わせて打錠した。下記の実施例から製造された一定含量のシルロスタゾール徐放錠を大韓薬典の溶出試験法によって溶出試験した。溶出液では、０.５Ｗ/Ｗ％のラウリル硫酸ナトリウム水溶液を使用し、溶出法は、パドル法、溶出液は、９００ｍｌ、撹拌速度は、７５ｒｐｍ、溶出温度は、３７±０.５℃で実行した。１５、３０、６０、９０、１２０、２４０、３６０、４８０、６００、７２０分に試料５ｍｌを取り同量の溶出液を加えた。分析条件は、上の溶出試験から得た液を０.４５μｍのメンブレンフィルターで濾過した液をＨＰＬＣを利用してシルロスタゾールを定量した。分析波長は、２５７ｎｍ、移動相は、アセトニトリル：水＝(４０：６０)混合液であり、オクタデシルシリル化したコラムを使用した。 Each formulation described in the table below produced sustained release tablets using the following production method. First, a binding solution was prepared by dispersing and dissolving in povidone K-30 and carbomer (50%) ethanol. Next, silrostazole, microcrystalline cellulose, carbomer (50%), and hydroxypropylmethylcellulose were mixed well using a speed mixer, and wet granules were produced with a cylindrical granulator using a binding solution. The produced granules are dried for 12 hours or more in a drying oven (40 ° C.) and sized with a 40 mesh sieve, and then added to and mixed with hard anhydrous silicic acid and magnesium stearate to the sized products. Tableting was performed according to the weight per tablet. A certain amount of sillostazol sustained-release tablets produced from the following examples was subjected to a dissolution test according to the dissolution test method of Korean Pharmaceutical. As eluent, 0.5 W / W% sodium lauryl sulfate aqueous solution is used, elution method is paddle method, eluent is 900 ml, stirring speed is 75 rpm, elution temperature is 37 ± 0.5 ° C. did. At 15, 30, 60, 90, 120, 240, 360, 480, 600, and 720 minutes, 5 ml of the sample was taken and the same amount of eluate was added. Analytical conditions were such that the liquid obtained from the above elution test was filtered through a 0.45 μm membrane filter, and sillostazol was quantified using HPLC. The analysis wavelength was 257 nm, the mobile phase was acetonitrile: water = (40:60) mixture, and an octadecylsilylated column was used.
(比較例１) (Comparative Example 1)
下記表に記載された各々の処方は、表に記載した成分で製造されるものの以外は実施例１と同様である。 Each prescription described in the following table is the same as that of Example 1 except that it is manufactured with the components described in the table.
(実施例２) (Example 2)
下記表に記載された各々の処方は、表に記載した成分で製造されるものの以外は実施例１と同様である。 Each prescription described in the following table is the same as that of Example 1 except that it is manufactured with the components described in the table.
(実施例３) Example 3
下記表に記載された各々の処方は、表に記載した成分で製造されるものの以外は実施例１と同様である。 Each prescription described in the following table is the same as that of Example 1 except that it is manufactured with the components described in the table.
(実施例４) Example 4
下記表に記載された各々の処方は、表に記載した成分で製造されるものの以外は実施例１と同様である。 Each prescription described in the following table is the same as that of Example 1 except that it is manufactured with the components described in the table.
(実施例５) (Example 5)
上記実施例から製造されたシルロスタゾール徐放錠の処方６、７、８、９を使用して、ｐＨに従う溶出試験を実施した。溶出液としては、各々大韓薬典の溶出試験法に記載されたｐＨ１.２(人工胃液)とｐＨ６.８(人工膓液)の０.５Ｗ/Ｗ％のラウリル硫酸ナトリウム水溶液を使用し、溶出法は、パドル法を使用した。溶出液量は、９００ｍｌ、撹拌速度は、７５ｒｐｍ、溶出温度は、３７±０.５℃で実行した。検液採取時間は、錠剤服用時に錠剤が一般的に胃で滞留する時間を規準とし、ｐＨ１.２で溶出試験した検体をｐＨ６.８で継続して溶出試験を実施した。検液採取は、試料５ｍｌを取り同量の溶出液を加えた。分析条件は、上の溶出試験から得た液を０.４５μｍのメンブレンフィルターで濾過した液をＨＰＬＣを利用してシルロスタゾールを定量した。分析波長は、２５７ｎｍ、移動相は、アセトニトリル：水＝(４０：６０)混合液であり、オクタデシルシリル化したコラムを使用した。
Dissolution tests according to pH were performed using
Claims (5)
カルボマー、ヒドロキシプロピルセルロース、メチルセルロース、ポリビニルピロリドン及びポリビニルアルコールから構成されたグループより選択された少なくとも１種以上の組合わせであるシルロスタゾール徐放錠。 A sillostazol sustained release tablet comprising sillostazol, a controlled release polymer, a binder, a filler and a lubricant, wherein the controlled release polymer is hydroxypropyl methylcellulose, and carbomer, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone And a sillostazol sustained-release tablet which is a combination of at least one selected from the group consisting of polyvinyl alcohol.
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